1. Field of the Invention
This invention comprises novel substituted tetronic acid type compounds, 2,4-(3H,5H)-furandiones, that are useful for the inhibition of the HIV protease enzyme. The compounds may be useful for the treatment of a person with AIDS or AIDS related diseases. The compounds may be used in the attempt to retard the further replication of any retrovirus containing the aspartyl protease enzyme.
2. Information Disclosure
PCT/US94/09533, filed Sep. 7, 1994.
WO 93/04055, published Mar. 4, 1993, inventor Dolak, Lester, et al. A tetronic acid useful for the inhibition of HIV-protease.
EP 0,259,707-A2 published Mar. 16, 1988, assigned to Takeda Chemical; Terao, Shinji et al., Hydroxybutenolide Derivatives useful for scavenging active oxygen species.
JP 05043568-A (90JP-202268) published Feb. 23, 1993, assigned to Takeda Chemical, disclosing tetronic acids used to treat inflammatory diseases.
Rehse, K., et al., "Anticoagulant Activity of 3,5-Disubstituted Tetronic Acids," Arch. Pharm. (Weinheim) Vol. 311, pp. 986-992 (1978).
Rehse, K., and Wagenknecht, J., "Mass Spectrometric Investigation of Anticoagulant 3-(1-Arylpropyl)-tetronic Acids," Arch. Pharm. (Weinheim), Vol. 312, pp. 164-168 (1979).
Rehse, K., et al., "Protein Binding of Drugs Determined by Continuous Ultrafiltration, III: Protein Binding of Anticoagulant Tetronic Acids," Arch. Pharm. (Weinheim) Vol. 315, pp. 052-056 (1982).
EP 0,534,907-A1, (92JP-276543) published Mar. 31, 1993, assigned to Nippon Zoki Pharmaceutical disclosing 2-(5H)-furanones to treat auto-immune diseases.
J. Synthetic Org. Chem. Japan, Vol. 44, No. 2, pp. 127- (1986).
Vekemans, J., "An Efficient Synthesis of (S)-5-Hydroxymethyl-2(5H)-Furanone" Tetrahedron Letters, Vol. 28, No. 20, pp. 2299-2300 (1987).
J. Org. Chem., Vol. 46, pp. 2299- (1981).
Kokai Number Hei-4-211676, published Aug. 3, 1992; Yoji, Shirokura. A tetronic acid useful as a vasodilator.
Roggo, B. E., et al., "3-Alkanoyl-5-Hydroxymethyl Tetronic Acid Homologues and Resistomycin: New Inhibitors of HIV-1 Protease, I. Fermentation, Isolation and Biological Activity" J. of Antibiotics, Vol. 47, No. 2, pp. 136-142 (Feb. 1994).
Roggo, B. E., et al., "3-Alkanoyl-5-Hydroxymethyl Tetronic Acid Homologues and Resistomycin: New Inhibitors of HIV-1 Protease, II. Structure Determination" J. of Antibiotics, Vol. 47, No. 2, pp. 143-147 (February 1994).
Lang, Marc and Roesel, Johannes, "HIV-1 Protease Inhibitors: Development, Status and Potential Role in the Treatment of AIDS," Archives of Pharmacy, Vol. 326, pp. 921-924 (1993). Undisclosed tetronic acid-type compounds thought to be possible HIV-1 protease inhibitor.
Chemical Abstracts, Vol. 98: 119144p (1983) page 20, anticoagulant activity of 3-arylalkyl-5-phenyl tetronic acids. 10 tetronic acid derivatives. Registry number of one compound is 80936-00-1, CA index name, 2(5H)-Furanone, 3-(1-(4-chlorophenyl)ethyl)-4-hydroxy-5-methyl-(9CI).
Chemical Abstracts, Vol. 90: 185907a (1979) page 575, Mass spectrometric investigation of anticoagulant 3-(1-arylpropyl) tetronic acids. Tetronic acid derivatives. Registry number of one compound, 69354-72-9, CA index name, 2(5H)-Furanone, 4-hydroxy-5-methyl-3-(1-phenylpropyl)-(9CI).
Chemical Abstracts, Vol. 90: 114925u (1979) page 28, Anticoagulant activity of 3-5-disubstituted tetronic acids. Tetronic acid derivatives. Registry number of one compound, 69354-71-8, CA index name, 2(5H)-Furanone, 3-(1-(4-chlorophenyl)propyl)-4-hydroxy-5-methyl-(9CI).
Chemical Abstracts, Vol. 55, Column 16687, paragraph f, disclosure of 3-(1-aminoethyl)-5-methyltetronic acid. Registry number 89910-36-1. CA index name, valeric acid, 2-(1-aminoethyl)-4-hydroxy-3-oxo, .gamma.-lactone (6CI, 7CI).
Fell, S. C. M. et al. "Synthesis of 4-Substituted Tetronic Acids: Multicolanic Acid." J. Chem. Soc., Chem. Commun., Vol. 2, pp. 81-2 (1979).
Chemical Abstracts, Vol. 34, Alicyclic Compounds (1963), Column 2378, paragraph f, disclosure of ethyl and methyl benzyltetronic acid. Registry number 91910-33-7. CA index name, valeric acid, 2 ethyl-4-hydroxy-3-oxo-5-phenyl, .gamma.-lactone (7CI).
Chemical Abstracts, Vol. 118: 45729r (1993) page 457, vasodilators containing terpenes, Registry number 145298-30-2, -29-9, -28-8, -27-7 CA index names, 2(5H)-Furanone, 3-(3,7-dimethyl-2,6octadienyl)-4-hydroxy-5-(3-methyl-2-butenyl)-(9CI); 2(5H)-Furanone, 3-(3,7-dimethyl-2,6octadienyl)-4-methoxy-5-(3-methyl-2-butenyl)-(9CI); 1,3-Pentanedione, 1-(4-(3,7-dimethyl-2,6-octadienyl)-2,5-dihydro-3-methoxy-2-(3-methyl-2-but enyl)-5-oxo-2-furanyl)-4-methyl-2-(3-methyl-2-butenyl)-(9CI); 1,3-Pentanedione, 1-(4-(3,7-dimethyl-2,6-octadienyl)-2,5-dihydro-3-hydroxy-2-(3-methyl-2-but enyl)-5-oxo-2-furanyl)-4-methyl-2-(3-methyl-2-butenyl)-(9CI).
Sibi, M. P. et al., "A Convenient Synthesis of 3-alkyltetronic acids from 3-acyltetronic acids." Synthetic Communications, Vol. 22, No. 6, pp. 809-816 (1992). Reductive deoxygenation of 3-acyltetronic acids provides 3-alkyltetronic acids in high yields. CA index names, 2(5H)-Furanone, 4-hydroxy-5-methyl-3-(2-methylpropyl)-, (S)-(9CI); 2(5H)-Furanone, 3-butyl-4-hydroxy-5-methyl, (S)-(9CI); 2(5H)-Furanone, 4-hydroxy-5-methyl-3-propyl-, (S)-(9CI); 2(5H)-Furanone, 3-ethyl-4-hydroxy-5-methyl, (S)-(9CI).
Arai, K., et al. "Metabolites of Penicillium italicum Wehmer: Isolation and Structures of New Metabolites Including Naturally Occurring 4-ylidene-acyltetronic Acids, Italicinic Acid and Italicic Acid." Chem Pharm. Bull., Vol. 37, No. 12, pp. 3229-3235 (1989). Isolation of 4 metabolites from bacteria. CA index name, 2-Furanacetic acid, 2,5-dihydro-3-hydroxy-4-(4-methyloctyl)-5-oxo-(9CI); 2-Furanacetic acid, 2,5-dihydro-3-hydroxy-4-(4-methyloctyl)-5-oxo-(9CI); Registry number 126228-72-6.
Wakabayashi, S., "Synthesis of Optically Active Litsenolide C." The Chemical Society of Japan. Chemistry Letters (5) (1987) pp. 875-878. CA index name, 2(5H)-Furanone, 4-hydroxy-5-methyl-3-tetradecyl-(R)-(9CI); Registry number 111722-91-9.
Buck, J. "Directed Metallations of 4-Ethylidenetetronic Acid O-Methyl Ether and its Derivatives as a Synthetic Entry to Natural 4-Oxyfuran-2-ones." J. Chem. Soc. Perkin Trans 1, Vol. 11, pp. 2399-2405 (1985).
Vanwagenen, B. S. "Native American Food and Medicinal Plants." Tetrahedron, Vol. 42, No. 4, pp. 1117-22. CA index names, 2(5H)-Furanone, 3-hexadecyl-4-hydroxy-5-methyl-(9CI); 2(5H)-Furanone, 3-tetradecyl-4-hydroxy-5-methyl-(9CI).
Chemical Abstracts, Vol. 97: 109463g (1982) Vinyl carbanions. Registry number 82495-62-3 CA index names, 2(5H)-Furanone, 3-(1-hydroxypropyl)-4-methoxy-5-(1-methylethyl)-(9CI).
Anderson, J. R., "Metabolites of Higher Fungi . . . " J. Chem. Soc., Perkin Trans. 1, Vol. 1, pp. 215-221. CA index name, 2(5H)-Furanone, 3-ethyl-4-hydroxy-5-propyl-(9CI). CA registry number 818608-84-6.
Chemical Abstracts, Vol. 87: 184299e (1977). Synthesis of 3,5-didodecyltetronic acid by ozonolysis of 2,6-didodecyl-3,5-dihydroxy-1,4-benzoquinone. Registry number 64580-85-4 CA index name, 2(5H)-Furanone, 3,5-didodecyl-4-hydroxy-(9CI).
Damon, R. E., et al. "A general synthesis of 2-alkyltetronic acids" Tetrahedron Letters, Vol. 32, pp. 2749-2752. CA index names, 3-Furanacetic acid, 5-butyl-2,5-dihydro-4-hydroxy-2-oxo, methyl ester (9CI), 2(5H)-Furanone, 4-hydroxy-5-methyl-3-(2-methylpropyl)-(9CI); 2(5H)-Furanone, 3-ethyl-4-hydroxy-5-methyl-(9CI); 2(5H)-Furanone, 4-hydroxy-5-methyl-3-(2-propenyl)-(9CI).
Gudgeon, J. A., et al., "The Structures and Biosynthesis of Multicolanic, Multicolic, and Multicolosic Acis, Novel Tetronic Acid Metabolites of Penicillium Multicolor." Bioorganic Chemistry, Vol. 8, pp. 311-322 (1979). CA index name, 2-Furanacetic acid, 2,5-dihydro-3-hydroxy-4-(5-hydroxypentyl)-5-oxo-(9CI).
Gudgeon, J. A., et al., "Use of singly and doubly labeled carbon-13-acetate in the elucidation of the structures and biosynthesis of multicolic and multicolosic acids, new tetronic acids from Penicillium multicolor." J. Chem. Soc., Chem. Commun., Vol. 16, pp. 636-8 (1974). Sudo, R., et al., "Synthesis of Carolic Acid," J. Org. Chem., Vol. 32, No. 6, pp. 1844-6. CA67(5):21426s.
Chemical Abstracts, registry number 6232-63-9, CA index name, 2,4(3H,5H)-Furandione, 3-(2-iminoethyl)-5-methyl-(8CI, 9CI).
Chemical Abstracts, Vol. 63, Column 13064, paragraph "a," (1965), registry number 4697-28-3, CA index name, 2-Furanacetic acid, 4-heptyl-2,5-dihydro-3-hydroxy-.alpha.-(3-methyl-2-butenylidene)-5-oxo-.(9 CI).
EP 0,365,329 A2, published Apr. 25, 1990, inventor, Matsumoto, Koichi; et al. Antiobiotics active against Anaerobic Bacteria, their production and use, and strains of Enterobacter producing the same.
EP 0,202,589 A2, published Nov. 26, 1986, inventor, Terao, Shinji; Ascorbic acid derivatives, production and use.
EP 0,480,624 A1, published Apr. 15, 1992, inventor, Treiber, Lazsio; et al., A novel dipeptide isostere inhibits HIV protease.
All the above documents are incorporated by reference herein.
3. Scientific and Historical Background
AIDS is a disease that is characterized by a severe immune deficiency primarily caused by a decreased cell-mediated immune response. Gottlieb, et al., N. Engl. J. Med., 305: 1425-1431 (1981); Masur, et al., N. Engl. J. Med., 305: 1431-1438 (1981). The immunodeficient state is characterized by a decrease in T4 lymphocytes, also known as helper T cells, a reversal of the normal T4&lt;+&gt;:T8&lt;+&gt; cell ratio, lymphopenia, and opportunistic infections often caused by Pneumocystis carinii. Some patients also develop lymphoma or Kaposi's sarcoma at increased incidence. The disease is usually fatal.
The virus that the majority of scientists believes causes AIDS, first identified in 1983, has been described by several names. It is the third known human T-lymphotropic virus (HTLV-III) and has the capacity to replicate within cells of the immune system and thereby lead to a profound destruction of T4&lt;+&gt; T-cells (or CD4&lt;+&gt; cells). See, e.g., Gallo, et al., Science, 224: 500-503 (1984), and Popovic, et al., Science, 224: 497-500 (1984). This retrovirus has been known as lymphadenopathy-associated virus (LAV) or AIDS-related virus (ARV) and, more recently, as human immunodeficiency virus (HIV).
Two distinct AIDS viruses, HIV-1 and HIV-2, have been described. HIV-1 is the virus originally identified in 1983 by Montagnier and co-workers at the Pasteur Institute in Paris. Montagnier, et al., Ann. de Virologie, 135 E: No. 1, 119-134 (1984), while HIV-2 was more recently isolated by Montagnier and his coworkers in 1986. Guyader, Nature, 326: 662-669 (1987). Additional distinct AIDS viruses may exist. As used herein, HIV is meant to refer to all of these viruses in a generic sense.
Retroviruses are enveloped RNA viruses. See, Hayward and Neel, Curr. Top. Microbiol. Immunol., 91: 217-276 (1981). The virus particle consists of a ribonucleoprotein core enclosed by an outer membrane envelope. Viral envelope glycoproteins protrude from the outer envelope. The viral genome consists of two identical single-stranded RNA molecules. Haseltine and Wong-Stall, Scientific American, 259: 52-62 (1988).
U.S. Pat. No. 4,724,232 claims a method of treating humans having AIDS utilizing 3-azido-3-deoxythymidine. On Mar. 20, 1987, the FDA approved the use of this compound, zidovudine (AZT), to treat AIDS patients with a recent initial episode of pneumocystis carinii pneumonia and for treatment of patients infected with the virus with an absolute CD4 lymphocyte count of less than 200/mm.sup.3 in the peripheral blood. AZT is a known inhibitor of viral reverse transcriptase.
Reverse transcriptase (RT) is an enzyme unique to retroviruses that catalyzes the conversion of viral RNA into double stranded DNA. Blockage at any point during the transcription process, by AZT or any other aberrant deoxynucleoside triphosphate incapable of elongation, is postulated to have dramatic consequences relative to viral replication, although no such therapy has yet been perfected.
Another approach to AIDS therapy focuses on the principal receptor on the T4 cell that the HIV seems to prefer to bind to, the so-called CD4 molecule. This molecule, a nonpolymorphic surface glycoprotein, has been targeted as an intervention point in AIDS therapy. Fisher, et al., Nature, 331: 76-78 (1988); Hussey, et al., Nature, 331: 78-81 (1988); and Deen, et al., Nature, 331: 82-84 (1988).
The present invention concerns a different therapeutic target in AIDS, the inhibition of the viral protease (or proteinase) that is essential for processing HIV-fusion polypeptide precursors. In HIV and several other retroviruses, the proteolytic maturation of the gag (group specific antigen) and gag/pol (polymerase) fusion polypeptides (a process indispensable for generation of infective viral particles) has been shown to be mediated by a protease that is, itself, encoded by the pol region of the viral genome. Yoshinaka, et al., Proc. Natl. Acad. Sci., USA, 82: 1618-1622 (1985); Yoshinaka, et al., J. Virol., 55: 870-873 (1985); Yoshinaka, et al., J. Virol., 57: 826-832 (1986).
The protease (or proteinase) enzyme, consisting of only 99 amino acids, is among the smallest enzyme known. Nutt, et al., Proc. Natl. Acad. Sci., USA, 85: 7129-7133 (1988). Pearl and Taylor, Nature, 329: 351-354 (1987). The three-dimensional structure and mechanism of the enzyme is known. Pearl and Taylor, Nature, 329: 351-354 (1987). Active HIV protease has been expressed in bacteria (e.g., Darke, et al., J. Biol. Chem., 264: 2307-2312 (1989)) and chemically synthesized. Schneider and Kent, Cell, 54: 363-368 (1988); and Nutt, et al., Proc. Natl. Acad. Sci., USA, 85: 7129-7133 (1988). All the above documents are incorporated by reference herein.
This invention comprises novel tetronic acid type compounds that are useful for the inhibition of the HIV protease enzyme. The compounds may be useful for the treatment of a person with AIDS or AIDS related diseases. The compounds may be used in the attempt to retard the further replication of any retrovirus containing the aspartyl protease enzyme or the human retrovirus such as HIV or of treating human cell systems especially including a patient infected with a human retrovirus containing the aspartyl protease enzyme.